4-alkyl-1-(cyclic imidoalkyl) piperidines



United States Patent 3,171,839 4-ALKYL-1-(CYCLIC IMIDOALKYL) PIPERIDINES Kurt J. Rorig, Glenview, Ill., assignor to G. D. Searle & Co., Chicago, 111., a corporation of Delaware No Drawing. Filed May 18, 1961, Ser. No. 110,852 8 Claims. (Cl. 260-294) This invention relates to 4-alkyl-l-(cyclic imidoalkyl) piperidines and processes for the manufacture thereof. More particularly, this invention relates to chemical compounds of the formula alkyleneN \R alkyl wherein the alkyl radical called for optimally (but not exclusively) contains fewer than 14 carbon atoms, the alkylene radical called for optimally (but not exclusively) contains fewer than 3 carbon atoms, and R represents the hydrocarbon residue of a cyclic imide.

Illustrative of alkyl radicals optimally adapted to the purposes of this invention are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, and isomeric straightand branch-chain hydrocarbon groupings of the formula n 2n+1 wherein n represents a positive integer less than 14. Correspondingly preferred alkylene radicals are methylene and ethylene, which is to say groupings of the formula 2)x wherein x represents 1 or 2. Alkyl and alkylene radicals, both straightand branched-chain, of higher than optimal carbon content are also within the purview of the described invention, albeit not individually named nor incorporated in the examples hereafter by reason of the greater interest which naturally attaches to maximally select species.

The hydrocarbon residues represented by R are most desirably saturated, as for example those derived from succinimide, glutarimide, alkyl-substituted succinimides and glutarimides such as pyrotartarimide and 4-ethyl-4- methylglutarimide, l,2-cyclohexanedicarboximide, etc., or preponderantly saturated as in the circumstance of their derivation from 1,2 cyclohexenedicarboximides. It follows from the above that R commonly but not necessarily exclusively represents a 2- or 3-carbon alkylene radical optimally substituted by 1 or more alkyl radicals and/or forming part of a substantially non-aromatic carbocycle.

The compounds to which this invention relates are useful because of their valuable and unexpected pharmacological properties. Among other things, they are anorectic agents, as also antibiotics characterized by a potent and various inhibitory effect on the growth of fungi such as Trichophylon mentagrophytes and bacteria such as B. subtilis and E. coli. Moreover, the claimed compounds operate to reduce the heat, swelling, and redness associated with the inflammatory response to tissue injury.

Manufacture of the imidomethyl products hereof proceeds by heating an appropriate imide 3,171,839 Patented Mar. 2, 1965 and piperidine Zl l alkyl with formalin, R being defined as before. An inert solvent, such as ethanol, is ordinarily employed, the reaction time ranging from a few minutes to perhaps as much as 1 hour. Imidoalkyl products wherein the alkyl constituent is ethyl or a higher homolog are similarly prepared from a corresponding w-haloalkylimide alkylene-Br the formalin, however, being omitted from the reaction mixture and an equivalent amount of potassium carbonate being introduced as an acid-binding agent. The time of the latter reaction is of the order of 48 hours, a solvent of choice being butanone.

The following examples describe in detail compounds illustrative of the present invention and methods which have been devised for their manufacture. However, the invention is not to be construed as limited thereby, either in spirit or scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practiced without departing from the purpose and intent of this disclosure. Throughout the examples hereinafter set forth, temperatures are given in degrees centigrade, pressures in millimeters of mercury, and relative amounts of materials in parts by weight, except as otherwise noted.

Example 1 4-methyl-1-succinimid0methylpiperidine.To a mixture of 20 parts of succinimide, 20 parts of 4-methylpiperidine, and 17 parts of 36% formalin is added 1 part of a concentrated aqueous solution of potassium carbonate. The resultant mixture is heated at about 99 for approximately minutes, following which it is filtered hot and the filtrate chilled to induce precipitation. The white waxen precipitate thrown down is separated by filtration, dried in air, and then recrystallized from pentane, affording iridescent flakes of 4-methyl-l-succinimidomethylpiperidine melting at approximately 87.588.5. The product has the formula Example 2 4 methyl 1 (3 methylsuccinimidomethyl)piperidine.Substitution of 24 parts of pyrotartarimide for the succinimide called for in Example 1 alfords, by the procedure there detailed, 4-methyl-l-(3-methylsuccinimidomethyl)piper-idine, of the formula CH4 ,l L. N

CHa

Example 3 (A) 4-tert-butylpiperidine.-A solution of 125 parts of 4-tert-butylpyridine in 1000 parts of aqueous 75% acetic acid is maintained with agitation in the presence of 4 parts of platinum oxide catalyst under approximately 34 atmospheres of hydrogen at about 55 until hydrogen uptake indicates that saturation of'the pyridine ring is accomplishedrepresen-tatively, after 12-hours. Catalyst is then filtered off, solvent distilled, and the residual oil partitioned between 500 parts of concentrated sodium hydrox-ide and 800 parts of ether. The ethereal phase is separated and dried over anhydrous potassium carbonate, whereupon solvent is evaporated and the residue distilled in vacuo. The distillate coming over at 7075/ 17 mm. is 4-tert-butylpiperidine which, being disposed to react with atmospheric carbon dioxide, is preserved under nitrogen.

(B) 4 tert butyl I succinimidomethyIpiperidine.- To a solution of 11 parts of succinimide in 80 parts of absolute ethanol is added 14 parts of 4-tert-butylpiperidine and 18 parts of 36% formalin. The resultant mixture is heated at approximately 90 for 15 minutes, then filtered hot. The filtrate is chilled and let stand to permit precipitation. The colorless felt-like needles thrown down are filtered off and washed with a small amount of ice-cold ethanol. The material thus isolated is 4-tert-butyl-1-succinimidomethylpiperidine melting at approximately 136-137". The product has the formula Example 4 4-nonyl-1-succinimidomethylpiperid-ine melting at approximately 80-81. The product has the formula 4 Example 5 (A) 4-decylpyridine.-To a suspension of 19 parts of sodamide in 700 parts of liquid ammonia is added, with agitation during 30 minutes, 45 parts of 4-methylpyridine. A solution of 100 parts of nonyl bromide in 100 parts of ether is then added with agitation during 1 hour. The resultant mixture is maintained with agitation for 4 hours, whereupon 300 parts of ether is introduced and the ammonia then allowed to evaporate overnight, agitation being continued throughout. The residue is decomposed by addition of 200 parts of water. The ether phase is separated, washed with water, and extracted with dilute hydrochloric acid. The extract is made basic with concentrated aqueous sodium hydroxide and extracted, in turn, with ether. Solvent is removed from the ether extract and the residue distilled in vacuo. The distillate coming over at 127132/0.S mm. is the desired 4-decylpyridine.

(B) 4-decylpiperidine.-To a solution of 76 parts of 4- decylpyridine in 800 parts of ethanol is added 8 parts of 5% ruthenium-on-carbon' catalyst. The resultant mixture is maintained with agitation at about 120 under approximately 34 atmospheres of hydrogen until saturation of the pyridine ring is complete, represent-atively, after 5 hours. Catalyst is then filtered 0E and the solvent distilled, whereupon the residue is distilled in vacuo. The fraction boiling at 96-110/0.2 mm. is the desired 4- decylpiperidine.

(C) 4 decyl 1 succinimidomethylpiperidine.T0 a solution of 45 parts of succinimide in 400 parts of absolute ethanol is added parts of 4-decylpiperidine and 74 parts of 36% formalin. The resultant mixture is heated at approximately 90 for 15 minutes, following which it is filtered hot, chilled, and let stand to permit precipitation. The colorless matted felt-like needles thrown down are separated by filtration and washed with 75 parts of ice-cold ethanol. The product thus isolated is 4-decyl-1-succinimidomethylpiperidine melting at 71- 75". It has the formula 1 z-o-zj l E Example 6 (C) 4 undecyl 1 succinimidomethylpiperidine.

Substitution of parts of 4-undecylpiperidine for the 4-decylpiperidine called for in Example 5C affords, by the procedure there detailed, 4-undecyl-l-succinimidomethylpiperidine melting at 83-85. the formula The product has Example 7 Dm Hz Example 8 4 decyl 1 glutarimid0methylpiperidine.To a solution of 51 parts of glutarimide in 400 parts of absolute ethanol is added 90 parts of 4-decylpiperidine and 74 parts of 36% formalin. The resultant mixture is heated at approximately 90 for minutes, whereupon it is filtered hot, chilled, and let stand to permit precipitation. The colorless matted needles thrown down are filtered off and washed with 50 parts of ice-cold ethanol. The product thus isolated is 4-decyl-l-glutarimidomethylpiperidine, melting at 68-73 and having the formula 0 O N a N MCH:

Example 9 1 glutarimidomethyl 4 undecylpiperidine.Substitution of 95 parts of 4-undecylpiperidine for the 4-decylpiperidine called for in Example 8 affords, by the procedure there detailed, l-glutarimidomethyl '4 undecyl- 6 piperidine melting at 67-72". The product has the formula 0 o N AH, 111

HzhoCE-x Example 10 1 -glutarimid0n1ethyl-4E-tridecylpiperia'ine.-Substitution of 107 parts of 4-tridecylpiperidine for the 4-decylpiperidine called for in Example 8 aifords, by the procedure there detailed, l-glutarimidomethyl 4 tridecylpiperidine melting at 62-70". The product has the formula z-o-Z (AHQHCHJ Example 11 (A) N-(Z-bromoethyl)glutarimide.-To a solution of V 2.3 parts of glutarimide in 160 parts of absolute ethanol is added a solution of 5 parts of sodium in 110 parts of absolute ethanol. Solvent is removed by distillation at reduced pressures, and to the solid residue is added parts of 1,2-dibromoethane. The resultant mixture is heated at the boiling point under reflux for 17 hours, then cooled to room temperature and filtered. Excess dibromoethane is removed from the filtrate by vacuum distillation; and the residue, a viscous oil, is extracted witha mixture of heptanes boiling in the range 77115. Distillation of solvent from this extract leaves as the residue N-(2- bromoethyl)glutarimide.

(B) 4-butyl-1-(2 -glutarimidoethyl)piperidine.-To a solution of 7 parts of 4-butylpiperidine and 11 parts of N-(2-bromethyl)glutarimide in 40 parts of butanone is added 3 parts of powdered anhydrous potassium carbonate. The resultant mixture is heated with agitation at the boiling point of the solvent under reflux for 48 hours, then freed of insoluble matter by filtration and stripped of solvent by distillation. The residue is taken up in 5% hydrochloric acid. The acid solution is washed with ether, then saturated with an excess of potassium carbonate. The material salted out is extracted with a mixture of chloroform and ether, from which extract solvent is removed by distillation, leaving, as the residue the desired 4butyl-1 (2 glutarimido-ethyl)piperidine. The product has the formula H CzHg Example 13 1-(4-ethyI-4-methylglutarimidomethyl) 4 nonylpiperidine-Substitution of 17 parts of 4-nonylpiperidine for the 4-tert-butylpiperidine called for in Example 12 affords, by the procedure there detailed, 1-(4-ethyl-4-methylglutarimido-methyl)-4-nonylpiperidine as small white flakes melting at about 45-465". The product has the formula Example 14 4-tert-butyl-1.-(l,2 cyclohexanedicarboximidomethyl) piperidine.-Substitution of 16 parts of 1,2-cyclohexanedicarboximide for the succinimide called for in Example 3B affords, by the procedure there detailed, 4-tert-butyl- 1 (1,2 cyclohexanedicarboximidomethyl)piperidine as thick white plates melting at approximately 100-101. The product has the formula N (EH; 1

8 Example 15 1-(1,Z-cyclohexanedicarboximidomethyl) -4-nonylpiperidine-To a solution of 28 parts of 1,2-cyclohexanedicarboximide in 160 parts of absolute ethanol is added 31 parts of 4-nonylpiperidine and 32 parts of 36% formalin. The resultant mixture is heated at approximately for 10 minutes, whereupon sufficient water is introduced to induce turbidity. On cooling, crystalline 1-(1,2-cyclohexanedicarboximidomethyl)-4-nonylpiperidine is thrown down. The product is filtered off, washed off, washed with 25 parts of 50% ethanol, and dried in air. The white flakes thus obtained melt at 5759. The product has the formula Example 16 1-(1,2-cycl0hexanedicarboximia'omethyl) -4-decylpiperidine-To a solution of 69 parts of 1,2-cyclohexanedicarboximide in 400 parts of absolute ethanol is added 90 parts of 4-deeylpiperidine and 74 parts of 36% formalin. The resultant mixture is heated at approximately 90 for 15 minutes, then filtered hot, chilled, and let stand to permit precipitation. The colorless solid thrown down is filtered 01f and washed with 50 parts of ice-cold ethanol. The 1-(1,2-cyclohexanedicarboximid0methyl4-decylpiperidine thus obtained melts at 60-64 and has the formula Example 17 1 (1,2 cyclohexanedicarboximidomethyl) 4 undeeylpiperidine.-Substitution of parts of 4-undecylpiperidine for the 4-decylpiperidine called for in Example 16 affords, by the procedure there detailed, 1-(1,2-cyclohexanedicarboximidomethyl)-4-undecylpiperidine melting at 67-70. The product has the formula 910 11: Example 18 1-(1,2-cyclohexanedicarboximidome'thyl)-4 tridecylpi- 9 peridine.Substitution of 107 parts of 4-tridecylpiperidine for the 4-decylpiperidine called for in Example 16 affords, by the procedure there detailed, 1-(1,2-cyclohexanedicarboximidomethyl)-4-tridecylpiperidine melting at 687l. The product has the formula O- O N in, 1 1

zhi Ha Example 19 Example 20 1-(4-cycl0hexene-1,Z-dicarbbximidomethyl) 4-n0nylpiperidine.Substitution of 17 parts of 4-nonylpiperidine for the 4-tert-butylpiperidine called for in Example 19 affords, by the procedure there detailed, 1-(4-cyclohexene- 1,2-dicarboximidomethyl)-4-nonylpiperidine in the form of a white powder melting at approximately 7172. The product has the formula Example 21 1-(4-cyclohexene-L2 dicarboximidomethyl)-4-decylpiperidine.-To a solution of 68 parts of 4-cyclohexene- 1,2-dicarboximide in 400 parts of absolute ethanol is added parts of 4-decylpiperidine and 74 parts of 36% formalin. The resultant mixture is heated at approximately 90 for 15 minutes, following which it is filtered hot, chilled, and allowed to cool and precipitate. The colorless solid thrown down is recovered on a filter and washed with 50 parts of ice-cold ethanol. This material is -1-(4-cyclohexene-1,2-dicarboximidomethyl) 4 decylpiperidine, melting at 6974 and having the formula 0 O N lHg 1 Example 22 1-(4-cyclohexene-L2 dicarboximidomethyl)-4-undecylpiperidine.-Substitution of parts of 4undecylpiperidine for the 4-decylpiperidine called for in Example 21 affords, by the procedure there detailed, 1-(4-cyclohexene-l,Z-dicarboximidomethyl)- 4 undecylpiperidine melting at 7678. The product has the formula a) 10 B: Example 23 1-(4-cycl0hexene 1,2-dicarb0ximid0methyl)-4-tridecylpiperidine.--Subs'titution of 107 parts of 4-tridecylpipen'dine for the 4-decylpiperidine called for in Example 21 afiords, by the procedure there detailed, 1-(4-cyclohexene-l;2-dicarboximidomethyl) 4 tridecylpiperidine melting at 78-82". The product has the formula What is claimed is: 1. A compound of the formula alkyl 1 1 1 2 wherein the alkyl radical called for contains fewer than 6. 1-(4-cyclohexene-1,2-dicarboximidomethyl)-4-nonyl- 14 carbon atoms. piperidine.

2. 4-methyl-1-succinimidomethylpiperidine. 7. A compound of the formula 3. A compound of the formula o 0 N 0-. o I Hz): N N a.

my] 7 wherein the alkyl radical called for contains fewer than a y 14 carbon atoms and .1: represents a positive integer less than 3. v wherein the alkyl radical called for contains fewer than 4. 1-glutarimidomethyl-4-undecylpiperidine. 14 arbon atoms, A compound of the formula 8. 4-tert-butyl-l-(4 ethyl-4-methylglutarimidomethyl)- piperidine.

References Cited by the Examiner UNITED STATES PATENTS 0 3,017,416 1/62 Lo etal 260-294 5H, OTHER REFERENCES 1 X Che'rbuliez et al.: Helv. Chim. Acta, volume 8, pages Porszasz et al.: Chem. Abstracts, vol. 51, page 13187b 1957) alky] NICHOLAS S. RIZZO, Primary Exmainer.

wherein the alkyl radical called for contains fewer than IRVING MARCUS, DUVAL T. MCCUTCHEN, WAL- 14 carbon atoms. TER A. MODANCE, Examiners. 

1. A COMPOUND OF THE FORMULA 